Life Expectancy After Treatment of Metastatic Bone Disease: An International Trend Analysis.

INTRODUCTION: The decision to treat metastatic bone disease (MBD) surgically depends in part on patient life expectancy. We are unaware of an international analysis of how life expectancy among these patients has changed over time. Therefore, we asked (1) how has the life expectancy for patients treated for MBD changed over time, and (2) which, if any, of the common primary cancer types are associated with longer survival after treatment of MBD? METHODS: We reviewed data collected from 2000 to 2022 in an international MBD database, as well as data used for survival model validation. We included 3,353 adults who underwent surgery and/or radiation. No patients were excluded. Patients were grouped by treatment date into period 1 (2000 to 2009), period 2 (2010 to 2019), and period 3 (2020 to 2022). Cumulative survival was portrayed using Kaplan-Meier curves; log-rank tests were used to determine significance at P < 0.05. Subgroup analyses by primary cancer diagnosis were performed. RESULTS: Median survival in period 2 was longer than in period 1 ( P < 0.001). Median survival (at which point 50% of patients survived) had not been reached for period 3. Median survival was longer in period 2 for all cancer types ( P < 0.001) except thyroid. Only lung cancer reached median survival in period 3, which was longer compared with periods 1 and 2 ( P < 0.001). Slow-growth, moderate-growth, and rapid-growth tumors all demonstrated longer median survival from period 1 to period 2; only rapid-growth tumors reached median survival for period 3, which was longer compared with periods 1 and 2 ( P < 0.001). DISCUSSION: Median duration of survival after treatment of MBD has increased, which was a consistent finding in nearly all cancer types. Longer survival is likely attributable to improvements in both medical and surgical treatments. As life expectancy for patients with MBD increases, surgical methods should be selected with this in mind. LEVEL OF EVIDENCE: VI.

The human bone marrow plasma cell compartment in rheumatoid arthritis - Clonal relationships and anti-citrulline autoantibody producing cells.

A majority of circulating IgG is produced by plasma cells residing in the bone marrow (BM). Long-lived BM plasma cells constitute our humoral immune memory and are essential for infection-specific immunity. They may also provide a reservoir of potentially pathogenic autoantibodies, including rheumatoid arthritis (RA)-associated anti-citrullinated protein autoantibodies (ACPA). Here we investigated paired human BM plasma cell and peripheral blood (PB) B-cell repertoires in seropositive RA, four ACPA+ RA patients and one ACPA- using two different single-cell approaches, flow cytometry sorting, and transcriptomics, followed by recombinant antibody generation. Immunoglobulin (Ig) analysis of >900 paired heavy-light chains from BM plasma cells identified by either surface CD138 expression or transcriptome profiles (including gene expression of MZB1, JCHAIN and XBP1) demonstrated differences in IgG/A repertoires and N-linked glycosylation between patients. For three patients, we identified clonotypes shared between BM plasma cells and PB memory B cells. Notably, four individuals displayed plasma cells with identical heavy chains but different light chains, which may indicate receptor revision or clonal convergence. ACPA-producing BM plasma cells were identified in two ACPA+ patients. Three of 44 recombinantly expressed monoclonal antibodies from ACPA+ RA BM plasma cells were CCP2+, specifically binding to citrullinated peptides. Out of these, two clones reacted with citrullinated histone-4 and activated neutrophils. In conclusion, single-cell investigation of B-cell repertoires in RA bone marrow provided new understanding of human plasma cells clonal relationships and demonstrated pathogenically relevant disease-associated autoantibody expression in long-lived plasma cells.

Predicting survival of patients with spinal metastatic disease using PathFx 3.0 - A validation study of 668 patients in Sweden.

Introduction: PathFx is a computer-based prediction model for estimating survival of patients with bone metastasis. The model has been validated in several studies, but this is the first validation using exclusively patients with spinal metastases. Research question: Is PathFx 3.0 a tool useful for predicting survival for patients with spinal metastatic disease? Material and methods: 668 patients (67% male, median age 67 years) presenting with spinal metastases at two university hospitals in Sweden 1991-2014 were included. Of those, the majority (82%, n â€‹= â€‹551) underwent surgery. Data on all patients was analyzed with PathFx version 3.0, generating a probability of survival at 1, 3, 6, 12, 18 and 24 months. The predictions were compared to real survival data and the precision in estimation was evaluated with Receiver-Operating Characteristic curve (ROC) analysis where the Area Under Curve (AUC) was calculated. Brier score and decision curve analyses were also assessed. Results: The AUC for 1-, 3-, 6- and 12 months survival predictions were 0.64 (95% CI 0.5-0.71), 0.71 (95% CI 0.67-0.75), 0.70 (95% CI 0.66-0.77) and 0.74 (95% CI 0.70-0.78). For 18- and 24 months survival the AUC were 0.74 (95% CI 0.69-0.78) and 0.76 (95% CI 0.72-0.81). The Brier scores were all 0.23 or lower depending on the estimated survival time. Discussion and conclusion: PathFx 3.0 is a reasonably reliable tool for predicting survival in patients with spinal metastatic disease. As the PathFx computer model can be updated to reflect advancements in oncology, we suggest this type of model, rather than rigid point-based scoring systems, to be used for estimating survival in patients with metastatic spinal disease in the future.

Can a Bayesian belief network for survival prediction in patients with extremity metastases (PATHFx) be externally validated in an Asian cohort of 356 surgically treated patients?

BACKGROUND AND PURPOSE: Predicted survival may influence the treatment decision for patients with skeletal extremity metastasis, and PATHFx was designed to predict the likelihood of a patient dying in the next 24 months. However, the performance of prediction models could have ethnogeographical variations. We asked if PATHFx generalized well to our Taiwanese cohort consisting of 356 surgically treated patients with extremity metastasis. PATIENTS AND METHODS: We included 356 patients who underwent surgery for skeletal extremity metastasis in a tertiary center in Taiwan between 2014 and 2019 to validate PATHFx's survival predictions at 6 different time points. Model performance was assessed by concordance index (c-index), calibration analysis, decision curve analysis (DCA), Brier score, and model consistency (MC). RESULTS: The c-indexes for the 1-, 3-, 6-, 12-, 18-, and 24-month survival estimations were 0.71, 0.66, 0.65, 0.69, 0.68, and 0.67, respectively. The calibration analysis demonstrated positive calibration intercepts for survival predictions at all 6 timepoints, indicating PATHFx tended to underestimate the actual survival. The Brier scores for the 6 models were all less than their respective null model's. DCA demonstrated that only the 6-, 12-, 18-, and 24-month predictions appeared useful for clinical decision-making across a wide range of threshold probabilities. The MC was < 0.9 when the 6- and 12-month models were compared with the 12-month and 18-month models, respectively. INTERPRETATION: In this Asian cohort, PATHFx's performance was not as encouraging as those of prior validation studies. Clinicians should be cognizant of the potential decline in validity of any tools designed using data outside their particular patient population. Developers of survival prediction tools such as PATHFx might refine their algorithms using data from diverse, contemporary patients that is more reflective of the world's population.

Machine learning algorithms to estimate 10-Year survival in patients with bone metastases due to prostate cancer: toward a disease-specific survival estimation tool.

BACKGROUND: Prognostic indicators, treatments, and survival estimates vary by cancer type. Therefore, disease-specific models are needed to estimate patient survival. Our primary aim was to develop models to estimate survival duration after treatment for skeletal-related events (SREs) (symptomatic bone metastasis, including impending or actual pathologic fractures) in men with metastatic bone disease due to prostate cancer. Such disease-specific models could be added to the PATHFx clinical-decision support tool, which is available worldwide, free of charge. Our secondary aim was to determine disease-specific factors that should be included in an international cancer registry. METHODS: We analyzed records of 438 men with metastatic prostate cancer who sustained SREs that required treatment with radiotherapy or surgery from 1989-2017. We developed and validated 6 models for 1-, 2-, 3-, 4-, 5-, and 10-year survival after treatment. Model performance was evaluated using calibration analysis, Brier scores, area under the receiver operator characteristic curve (AUC), and decision curve analysis to determine the models' clinical utility. We characterized the magnitude and direction of model features. RESULTS: The models exhibited acceptable calibration, accuracy (Brier scores < 0.20), and classification ability (AUCs > 0.73). Decision curve analysis determined that all 6 models were suitable for clinical use. The order of feature importance was distinct for each model. In all models, 3 factors were positively associated with survival duration: younger age at metastasis diagnosis, proximal prostate-specific antigen (PSA) < 10 ng/mL, and slow-rising alkaline phosphatase velocity (APV). CONCLUSIONS: We developed models that estimate survival duration in patients with metastatic bone disease due to prostate cancer. These models require external validation but should meanwhile be included in the PATHFx tool. PSA and APV data should be recorded in an international cancer registry.

The obesity paradox and mortality after pathological hip fractures: a Swedish registry study.

Background and purpose - Obesity as measured by BMI has been associated with increased survival in various diseases, a phenomenon known as the "obesity paradox." It is unknown whether obesity is associated with survival after pathological fractures. We investigated the association between BMI and survival after surgery for pathological hip fracture, to improve survival prognostication, and lay grounds for further interventional nutritional studies. Patients and methods - We analyzed prospectively collected data from Swedish nationwide registry "RIKSHÖFT." The study cohort included 1,000 patients operated for a pathological hip fracture between 2014 and 2019. BMI registered on admission was available in 449 patients. Overall patient survival was measured according to the Kaplan-Meier method. Multivariable regression was used to evaluate association with other potential factors that influence patient survival. Results - Overweight and obesity were associated with an increased postoperative survival in male patients with surgically treated pathological hip fractures. Multivariable analysis considering potential confounders confirmed this finding. The association was not that strong in women and did not reach statistical significance. Interpretation - BMI, a commonly available clinical parameter, is a good predictor of overall survival for patients operated on for pathological hip fracture. Incorporation of BMI in existent survival prognostication algorithms should be considered. Treatment of malnutrition in this frail group of patients is worth studying.

Outcome of surgical treatment for bone metastases caused by colorectal cancer.

BACKGROUND: Cancer of the lower intestinal tract, although relatively common, rarely metastasizes to the skeleton. The treatment of metastatic bone disease due to colorectal cancer has thus been poorly described and treatment decisions are therefore difficult. The aim of this study was to describe the outcome of orthopedic surgery in patients with pathological fractures from colorectal cancer and investigate factors that correlate with patient survival, since it influences treatment decisions. METHODS: Retrospective review of data collected in a prospectively collected database. 36 patients (38 fractures) who underwent surgery between 2000 and 2019 for metastatic bone disease caused by colorectal cancer were included. RESULTS: Most metastases were localized in the axial skeleton and 33/36 patients already had visceral metastases. Patients with pathological fractures from colorectal cancer had poor prognosis, with only 5/36 surviving more than 1 year, median survival being 3 months. Patients presenting with a single skeletal metastasis had a superior overall survival (P≤0.001). Post-operative complications were common, noted in 11 patients, and the surgical failure rate was considerable. CONCLUSIONS: Although relatively rare, bone metastases should be suspected in patients with colorectal cancer presenting with signs and symptoms of spinal cord compression or skeletal pain. In this case, the presence of a solitary skeletal lesion is a favorable prognostic sign. Awareness for local complications after surgery should be high.

Prosthesis or osteosynthesis for the treatment of a pathological hip fracture? A nationwide registry-based cohort study.

AIMS: How endoprosthetic replacement compares to osteosynthesis in the treatment of pathologic hip fractures as far as functional outcome and use of healthcare resources is concerned remains largely unknown. We aimed to investigate this in a nationwide registry. METHODS: We analyzed the functional outcome after surgery for a pathological fracture of the hip in terms of post-operative pain and ambulatory capacity. The preferred surgical method depending on the level of the treating unit was also examined. Furthermore, we documented the length of hospital stay and the patterns of discharge and compared them between these two methods. RESULTS: Patients operated with an endoprosthesis reported significantly lower pain at follow-up. Both methods (endoprosthetic replacement and osteosynthesis) were equally effective in restoring the ambulatory capacity and demanded a similar length of stay in hospital. Orthopaedic surgeons working in hospitals with dedicated sarcoma teams were more likely to use a prosthesis rather than osteosynthesis, when compared to surgeons working at other university hospitals or emergency hospitals. CONCLUSION: Endoprosthetic replacement results in a better functional outcome in terms of post-operative pain without consuming more healthcare resources. Orthopaedic surgeons working in hospitals with sarcoma centers are more likely to use prostheses as compared to surgeons working at hospitals where dedicated musculoskeletal oncology teams are not available.

Surgical treatment of skeletal metastases in proximal tibia: a multicenter case series of 74 patients.

Background and purpose - The proximal tibia is a rare site for metastatic bone disease and is a challenging anatomical site to manage due to the proximity to the knee joint and poor soft tissue envelope. We investigated implant survival and complications of different surgical strategies in the treatment of proximal tibia pathological fractures.Patients and methods - The study comprised a 4 medical center, retrospective analysis of 74 patients surgically treated for metastases of the proximal tibia. Patient records were reviewed to identify outcome, incidence, and type of complications as well as contributing factors.Results - Reconstruction techniques comprised cement-augmented osteosynthesis (n = 33), tumor prosthesis (n = 31), and total knee arthroplasty with long cemented stems (n = 10). Overall implant survival was 88% at 6 months and 1 year, and 67% at 3 years. After stratification by technique, the implant survival was 82% and 71% at 1 and 3 years with tumor prosthesis, 100% at 1 and 3 years with total knee arthroplasty, and 91% at 1 year and 47% at 3 years with osteosynthesis. Preoperative radiotherapy decreased implant survival. Complications were observed in 19/74 patients. Treatment complications led to amputation in 5 patients.Interpretation - In this study, the best results were seen with both types of prothesis reconstructions, with good implant survival, when compared with treatment with osteosynthesis. However, patients treated with tumor prosthesis showed an increased incidence of postoperative infection, which resulted in poor implant survival. Osteosynthesis with cement is a good alternative for patients with short expected survival whereas endoprosthetic replacement achieved good medium-term results.

Validation of PATHFx 2.0: An open-source tool for estimating survival in patients undergoing pathologic fracture fixation.

Treatment decisions in patients with metastatic bone disease rely on accurate survival estimation. We developed the original PATHFx models using expensive, proprietary software and now seek to provide a more cost-effective solution. Using open-source machine learning software to create PATHFx version 2.0, we asked whether PATHFx 2.0 could be created using open-source methods and externally validated in two unique patient populations. The training set of a well-characterized, database records of 189 patients and the bnlearn package within R Version 3.5.1 (R Foundation for Statistical Computing), was used to establish a series of Bayesian belief network models designed to predict survival at 1, 3, 6, 12, 18, and 24 months. Each was externally validated in both a Scandinavian (n = 815 patients) and a Japanese (n = 261 patients) data set. Brier scores and receiver operating characteristic curves to assessed discriminatory ability. Decision curve analysis (DCA) evaluated whether models should be used clinically. DCA showed that the model should be used clinically at all time points in the Scandinavian data set. For the 1-month time point, DCA of the Japanese data set suggested to expect better outcomes assuming all patients will survive greater than 1 month. Brier scores for each curve demonstrate that the models are accurate at each time point. Statement of Clinical Significance: we successfully transitioned to PATHFx 2.0 using open-source software and externally validated it in two unique patient populations, which can be used as a cost-effective option to guide surgical decisions in patients with metastatic bone disease.

External Validation of PATHFx Version 3.0 in Patients Treated Surgically and Nonsurgically for Symptomatic Skeletal Metastases.

BACKGROUND: PATHFx is a clinical decision-support tool based on machine learning capable of estimating the likelihood of survival after surgery for patients with skeletal metastases. The applicability of any machine-learning tool depends not only on successful external validation in unique patient populations but also on remaining relevant as more effective systemic treatments are introduced. With advancements in the treatment of metastatic disease, it is our responsibility to patients to ensure clinical support tools remain contemporary and accurate. QUESTION/PURPOSES: Therefore, we sought to (1) generate updated PATHFx models using recent data from patients treated at one large, urban tertiary referral center and (2) externally validate the models using two contemporary patient populations treated either surgically or nonsurgically with external-beam radiotherapy alone for symptomatic skeletal metastases for symptomatic lesions. METHODS: After obtaining institutional review board approval, we collected data on 208 patients undergoing surgical treatment for pathologic fractures at Memorial Sloan Kettering Cancer Center between 2015 and 2018. These data were combined with the original PATHFx training set (n = 189) to create the final training set (n = 397). We then created six Bayesian belief networks designed to estimate the likelihood of 1-month, 3-month, 6-month, 12-month, 18-month, and 24-month survival after treatment. Bayesian belief analysis is a statistical method that allows data-driven learning to arise from conditional probabilities by exploring relationships between variables to estimate the likelihood of an outcome using observed data. For external validation, we extracted the records of patients treated between 2016 and 2018 from the International Bone Metastasis Registry and records of patients treated nonoperatively with external-beam radiation therapy for symptomatic skeletal metastases from 2012 to 2016 using the Military Health System Data Repository (radiotherapy-only group). From each record, we collected the date of treatment, laboratory values at the time of treatment initiation, demographic data, details of diagnosis, and the date of death. All records reported sufficient follow-up to establish survival (yes/no) at 24-months after treatment. For external validation, we applied the data from each record to the new PATHFx models. We assessed calibration (calibration plots), accuracy (Brier score), discriminatory ability (area under the receiver operating characteristic curve [AUC]). RESULTS: The updated PATHFx version 3.0 models successfully classified survival at each time interval in both external validation sets and demonstrated appropriate discriminatory ability and model calibration. The Bayesian models were reasonably calibrated to the Memorial Sloan Kettering Cancer Center training set. External validation with 197 records from the International Bone Metastasis Registry and 192 records from the Military Health System Data Repository for analysis found Brier scores that were all less than 0.20, with upper bounds of the 95% confidence intervals all less than 0.25, both for the radiotherapy-only and International Bone Metastasis Registry groups. Additionally, AUC estimates were all greater than 0.70, with lower bounds of the 95% CI all greater than 0.68, except for the 1-month radiotherapy-only group. To complete external validation, decision curve analysis demonstrated clinical utility. This means it was better to use the PATHFx models when compared to the default assumption that all or no patients would survive at all time periods except for the 1-month models. We believe the favorable Brier scores (< 0.20) as well as DCA indicate these models are suitable for clinical use. CONCLUSIONS: We successfully updated PATHFx using contemporary data from patients undergoing either surgical or nonsurgical treatment for symptomatic skeletal metastases. These models have been incorporated for clinical use on PATHFx version 3.0 (https://www.pathfx.org). Clinically, external validation suggests it is better to use PATHFx version 3.0 for all time periods except when deciding whether to give radiotherapy to patients with the life expectancy of less than 1 month. This is partly because most patients survived 1-month after treatment. With the advancement of medical technology in treatment and diagnosis for patients with metastatic bone disease, part of our fiduciary responsibility is to the main current clinical support tools. LEVEL OF EVIDENCE: Level III, therapeutic study.

What Factors Are Associated With Implant Breakage and Revision After Intramedullary Nailing for Femoral Metastases?

BACKGROUND: Actual and impending pathologic fractures of the femur are commonly treated with intramedullary nails because they provide immediate stabilization with a minimally invasive procedure and enable direct weightbearing. However, complications and revision surgery are prevalent, and despite common use, there is limited evidence identifying those factors that are associated with complications. QUESTIONS/PURPOSES: Among patients treated with intramedullary nailing for femoral metastases, we asked the following questions: (1) What is the cumulative incidence of local complications? (2) What is the cumulative incidence of implant breakage and what factors are associated with implant breakage? (3) What is the cumulative incidence of revision surgery and what factors are associated with revision surgery? METHODS: Between January 2000 and December 2015, 245 patients in five centers were treated with intramedullary nails for actual and impending pathologic fractures of the femur caused by bone metastases. During that period, the general indications for intramedullary nailing of femoral metastases were impending fractures of the trochanter region and shaft and actual fractures of the trochanter region if sufficient bone stock remained; nails were used for lesions of the femoral shaft if they were large or if multiple lesions were present. Of those treated with intramedullary nails, 51% (117) were actual fractures and 49% (111) were impending fractures. A total of 60% (128) of this group were women; the mean age was 65 years (range, 29-93 years). After radiologic followup (at 4-8 weeks) with the orthopaedic surgeon, because of the palliative nature of these treatments, subsequent in-person followup was performed by the primary care provider on an as-needed basis (that is, as desired by the patient, without any scheduled visits with the orthopaedic surgeon) throughout each patient's remaining lifetime. However, there was close collaboration between the primary care providers and the orthopaedic team such that orthopaedic complications would be reported. A total of 67% (142 of 212) of the patients died before 1 year, and followup ranged from 0.1 to 175 months (mean, 14.4 months). Competing risk models were used to estimate the cumulative incidence of local complications (including persisting pain, tumor progression, and implant breakage), implant breakage separately, and revision surgery (defined as any reoperation involving the implant other than débridement with implant retention for infection). A cause-specific multivariate Cox regression model was used to estimate the association of factors (fracture type/preoperative radiotherapy and fracture type/use of cement) with implant breakage and revision, respectively. RESULTS: Local complications occurred in 12% (28 of 228) of the patients and 6-month cumulative incidence was 8% (95% confidence interval [CI], 4.7-11.9). Implant breakage occurred in 8% (18 of 228) of the patients and 6-month cumulative incidence was 4% (95% CI, 1.4-6.5). Independent factors associated with increased risk of implant breakage were an actual (as opposed to impending) fracture (cause-specific hazard ratio [HR_cs], 3.61; 95% CI, 1.23-10.53, p = 0.019) and previous radiotherapy (HR_cs, 2.97; 95% CI, 1.13-7.82, p = 0.027). Revisions occurred in 5% (12 of 228) of the patients and 6-month cumulative incidence was 2.2% (95% CI, 0.3-4.1). The presence of an actual fracture was independently associated with a higher risk of revision (HR_cs, 4.17; 95% CI, 0.08-0.82, p = 0.022), and use of cement was independently associated with a lower risk of revision (HR_cs, 0.25; 95% CI, 1.20-14.53, p = 0.025). CONCLUSIONS: The cumulative incidence of local complications, implant breakage, and revisions is low, mostly as a result of the short survival of patients. Based on these results, surgeons should consider use of cement in patients with intramedullary nails with actual fractures and closer followup of patients after actual fractures and preoperative radiotherapy. Future, prospective studies should further analyze the effects of adjuvant therapies and surgery-related factors on the risk of implant breakage and revisions. LEVEL OF EVIDENCE: Level III, therapeutic study.

Can A Multivariate Model for Survival Estimation in Skeletal Metastases (PATHFx) Be Externally Validated Using Japanese Patients?

BACKGROUND: Objective survival estimates are important when treating or studying outcomes in patients with skeletal metastases. One decision-support tool, PATHFx (www.pathfx.org) is designed to predict each patient's postsurgical survival trajectory at 1, 3, 6, and 12 months in patients undergoing stabilization for skeletal metastases. PATHFx has been externally validated in various western centers, but it is unknown whether it may be useful in Asian patient populations. QUESTIONS/PURPOSES: We asked (1) whether the PATHFx models are as predictive in Japanese patients by estimating the area under the receiver operator characteristic curve (AUC); we considered an AUC greater than 0.7 as an adequate predictive value. We also (2) performed decision curve analysis at various times to determine whether and how PATHFx should be used clinically at those times. PATIENTS AND METHODS: A Bayesian model is a statistical method to explore conditional, probabilistic relationships between variables to estimate the likelihood of an outcome using observed data. We applied the PATHFx Bayesian models to an independent dataset containing the records of patients who underwent skeletal stabilization for metastatic bone disease at one of five Japanese referral centers and had a followup longer than 12 months for survivors. Of 270 patients in the database, we excluded nine patients from analysis because their followup was less than 12 months, and finally we included 261 patients in the analysis. Data examined included age at the time of surgery, sex, indication for surgery (impending fracture or completed pathologic fracture), number of bone metastases (solitary or multiple), presence or absence of visceral or lymph node metastases, preoperative hemoglobin concentration, absolute lymphocyte count, and the primary oncologic diagnosis. We performed receiver operating characteristic curve analysis and estimated the AUC as a measure of discriminatory ability. Decision curve analysis was performed to determine if and how the models should be used in the clinical setting. RESULTS: The AUCs for the 1-, 3-, 6-, and 12-month models were 0.77 (95% CI, 0.63-0.86), 0.80 (95% CI, 0.72-0.87), 0.83 (95% CI, 0.77-0.89), and 0.80 (95% CI, 0.75-0.86), respectively. Decision analysis indicated that the models conferred a positive net benefit (above the lines assuming none or all survive at each time) although the CIs of the AUC for 1 month were wide, suggesting that this dataset could not adequately predict 1-month survival. CONCLUSIONS: Our findings show PATHFx is suitable for clinical use in Japan and may be used to guide surgical decision making or as a risk stratification method in support of clinical trials involving Japanese patients at 3, 6, and 12 months. More studies will be necessary to confirm the validity of the 1-month survival predictions of this mode. Other patient populations will need to be studied to confirm its usefulness in other non-Western and non-Japanese populations. LEVEL OF EVIDENCE: Level II, prognostic study.

Can We Estimate Short- and Intermediate-term Survival in Patients Undergoing Surgery for Metastatic Bone Disease?

BACKGROUND: Objective means of estimating survival can be used to guide surgical decision-making and to risk-stratify patients for clinical trials. Although a free, online tool ( www.pathfx.org ) can estimate 3- and 12-month survival, recent work, including a survey of the Musculoskeletal Tumor Society, indicated that estimates at 1 and 6 months after surgery also would be helpful. Longer estimates help justify the need for more durable and expensive reconstructive options, and very short estimates could help identify those who will not survive 1 month and should not undergo surgery. Thereby, an important use of this tool would be to help avoid unsuccessful and expensive surgery during the last month of life. QUESTIONS/PURPOSES: We seek to provide a reliable, objective means of estimating survival in patients with metastatic bone disease. After generating models to derive 1- and 6-month survival estimates, we determined suitability for clinical use by applying receiver operator characteristic (ROC) (area under the curve [AUC] > 0.7) and decision curve analysis (DCA), which determines whether using PATHFx can improve outcomes, but also discerns in which kinds of patients PATHFx should not be used. METHODS: We used two, existing, skeletal metastasis registries chosen for their quality and availability. Data from Memorial Sloan-Kettering Cancer Center (training set, n = 189) was used to develop two Bayesian Belief Networks trained to estimate the likelihood of survival at 1 and 6 months after surgery. Next, data from eight major referral centers across Scandinavia (n = 815) served as the external validation set-that is, as a means to test model performance in a different patient population. The diversity of the data between the training set from Memorial Sloan-Kettering Cancer Center and the Scandinavian external validation set is important to help ensure the models are applicable to patients in various settings with differing demographics and treatment philosophies. We considered disease-specific, laboratory, and demographic information, and the surgeon's estimate of survival. For each model, we calculated the area under the ROC curve (AUC) as a metric of discriminatory ability and the Net Benefit using DCA to determine whether the models were suitable for clinical use. RESULTS: On external validation, the AUC for the 1- and 6-month models were 0.76 (95% CI, 0.72-0.80) and 0.76 (95% CI, 0.73-0.79), respectively. The models conferred a positive net benefit on DCA, indicating each could be used rather than assume all patients or no patients would survive greater than 1 or 6 months, respectively. CONCLUSIONS: Decision analysis confirms that the 1- and 6-month Bayesian models are suitable for clinical use. CLINICAL RELEVANCE: These data support upgrading www.pathfx.org with the algorithms described above, which is designed to guide surgical decision-making, and function as a risk stratification method in support of clinical trials. This updating has been done, so now surgeons may use any web browser to generate survival estimates at 1, 3, 6, and 12 months after surgery, at no cost. Just as short estimates of survival help justify palliative therapy or less-invasive approaches to stabilization, more favorable survival estimates at 6 or 12 months are used to justify more durable, complicated, and expensive reconstructive options.

Surgery of non-spinal skeletal metastases in renal cell carcinoma: No effect of preoperative embolization?

BACKGROUND AND PURPOSE: Surgery for metastases of renal cell carcinoma has increased in the last decade. It carries a risk of massive blood loss, as tumors are hypervascular and the surgery is often extensive. Preoperative embolization is believed to facilitate surgery. We evaluated the effect of preoperative embolization and resection margin on intraoperative blood loss, operation time, and survival in non-spinal skeletal metastases of renal cell carcinoma. PATIENTS AND METHODS: This retrospective study involved 144 patients, 56 of which were treated preoperatively with embolization. The primary outcome was intraoperative blood loss. We also identified factors affecting operating time and survival. RESULTS: We did not find statistically significant effects on intraoperative blood loss of preoperative embolization of skeletal non-spinal metastases. Pelvic localization and large tumor size increased intraoperative blood loss. Marginal resection compared to intralesional resection, nephrectomy, level of hemoglobin, and solitary metastases were associated with better survival. INTERPRETATION: Tumor size, but not embolization, was an independent factor for intraoperative blood loss. Marginal resection rather than intralesional resection should be the gold standard treatment for skeletal metastases in non-spinal renal cell carcinoma, especially in the case of a solitary lesion, as this improved the overall survival.

Femoral Metastasis from Penile Carcinoma: Report of 2 Cases.

Purpose. Penile cancer rarely gives symptomatic skeletal metastases. Methods. We present 2 patients with squamous carcinoma of the penis who were surgically treated for metastases in the femur. Results. Both patients had pathological fractures and were operated on. In one case, the skeletal metastasis preceded any lymphatic spread of the disease, suggesting early haematogenous dissemination. Conclusions. Endoprosthetic reconstruction resulted in pain relief and restored the ambulatory capacity. Clinicians should be aware of the possibility for symptomatic bone metastases with a risk for pathological fracture in patients with penile cancer.

Reconstruction of metastatic acetabular defects using a modified Harrington procedure.

BACKGROUND AND PURPOSE: Metastases engaging the acetabulum result in significant disability. We investigated the outcome after curettage and reconstruction of the defect with a protrusio cage, retrograde screws, and a cemented total hip arthroplasty. PATIENTS AND METHODS: We retrospectively identified 70 consecutive patients who were surgically treated for metastatic disease of the acetabulum between 1995 and 2012 using the above technique. The type of primary tumor, extent of the disease, degree of acetabular erosion, and type of implant used were identified. Patient and implant survival, complications, and functional outcome were recorded. RESULTS: There were no mortalities in the perioperative period (30 days after surgery). Median overall patient survival was 12 months. Prosthesis survival was 92% at 1 year and 89% at 5 years. One third of the patients suffered a complication, the most frequent one being dislocation. The functional outcome was good. Multiple skeletal or visceral metastases and specific types of cancer were associated with poor patient survival. INTERPRETATION: Reconstruction of metastatic acetabular defects using a protrusio cage stabilized with retrograde screws and a cemented total hip arthroplasty is a safe procedure that provides efficient relief of symptoms. Patients with extensive disease, especially when diagnosed with specific types of cancer, have a very poor prognosis. The complication rate is substantial, the most frequent being dislocation. However, revision surgery is seldom required and prosthesis survival is high.

How do we estimate survival? External validation of a tool for survival estimation in patients with metastatic bone disease-decision analysis and comparison of three international patient populations.

BACKGROUND: We recently developed a clinical decision support tool, capable of estimating the likelihood of survival at 3 and 12 months following surgery for patients with operable skeletal metastases. After making it publicly available on www.PATHFx.org , we attempted to externally validate it using independent, international data. METHODS: We collected data from patients treated at 13 Italian orthopaedic oncology referral centers between 2010 and 2013, then applied to PATHFx, which generated a probability of survival at three and 12-months for each patient. We assessed accuracy using the area under the receiver-operating characteristic curve (AUC), clinical utility using Decision Curve Analysis (DCA), and compared the Italian patient data to the training set (United States) and first external validation set (Scandinavia). RESULTS: The Italian dataset contained 287 records with at least 12 months follow-up information. The AUCs for the three-month and 12-month estimates was 0.80 and 0.77, respectively. There were missing data, including the surgeon's estimate of survival that was missing in the majority of records. Physiologically, Italian patients were similar to patients in the training and first validation sets. However notable differences were observed in the proportion of those surviving three and 12-months, suggesting differences in referral patterns and perhaps indications for surgery. CONCLUSIONS: PATHFx was successfully validated in an Italian dataset containing missing data. This study demonstrates its broad applicability to European patients, even in centers with differing treatment philosophies from those previously studied.

Prognostic role of en-bloc resection and late onset of bone metastasis in patients with bone-seeking carcinomas of the kidney, breast, lung, and prostate: SSG study on 672 operated skeletal metastases.

BACKGROUND AND OBJECTIVES: In metastatic disease, decisions regarding potential surgery require reliable data about the patient's survival. In this study, we evaluated different prognostic factors and their impact in four common primary tumors causing bone metastases. METHODS: Data were acquired from the Scandinavian Sarcoma Group (SSG) metastasis registry. The patients underwent surgery between July 1999 and July 2009. This study included breast, prostate, lung, and kidney cancer cases, with a total of 672 operated non-spinal metastases. Differences in prognostic factors were evaluated using the Kaplan-Meier method with long-rank test. Cox regression multivariate analysis was performed to identify statistically independent prognostic factors. RESULTS: Significant factors affecting survival were the presence of organ metastases, overall heath status, and disease load. In kidney cancer, en bloc resection of solitary metastases was associated with a significant fourfold longer survival compared to intralesional surgery. Preoperative radiotherapy was associated with higher complication and reoperation rates. CONCLUSIONS: This data summary is important tool for clinicians to evaluate survival and choose treatment options for patients suffering from metastatic bone disease.

Skeletal metastases in 301 breast cancer patients: patient survival and complications after surgery.

The aim was to identify prognostic variables associated with survival in 301 breast cancer patients after surgical treatment of skeletal metastases. The study period was 1986-2012. The median age at surgery was 61 (interquartile-range [IQR] 52-70) years. The cumulative 1-, 2-, and 5-year survival after surgery was 45% (95% CI 39-51), 27% (22-32), and 8% (5-12), respectively. The median follow-up time was 1 (IQR 0.2-2) year. Age over 60 years (Hazard ratio [HR] 1.9) and hemoglobin levels <110 g/L (HR 2) increased the risk of death after surgery. Patients with impending fractures (HR 0.4) had a lower death rate. The overall neurological function in patients with spinal metastases improved after surgery (p < 0.001). The complication rate was 25%, including 14% re-operations. Survival data and analysis of complications of this large cohort of surgically treated breast cancer patients help to set appropriate expectations for the patients, families, and medical staff.